Intrinsic Resistance to MEK Inhibition in KRAS Mutant Lung and Colon Cancer through Transcriptional Induction of ERBB3

There are no effective therapies for the ~30% of human malignancies with mutant RAS oncogenes. Using a kinome-centered synthetic lethality screen, we find that suppression of the ERBB3 receptor tyrosine kinase sensitizes KRAS mutant lung and colon cancer cells to MEK inhibitors. We show that MEK inh...

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Published in:	Cell reports (Cambridge) Vol. 7; no. 1; pp. 86 - 93
Main Authors:	Sun, Chong, Hobor, Sebastijan, Bertotti, Andrea, Zecchin, Davide, Huang, Sidong, Galimi, Francesco, Cottino, Francesca, Prahallad, Anirudh, Grernrum, Wipawadee, Tzani, Anna, Schlicker, Andreas, Wessels, Lodewyk F.A., Smit, Egbert F., Thunnissen, Erik, Halonen, Pasi, Lieftink, Cor, Beijersbergen, Roderick L., Di Nicolantonio, Federica, Bardelli, Alberto, Trusolino, Livio, Bernards, Rene
Format:	Journal Article
Language:	English
Published:	United States Elsevier 01.04.2014
Subjects:	Animals Apoptosis - genetics Cell Line, Tumor Colonic Neoplasms - drug therapy Colonic Neoplasms - enzymology Colonic Neoplasms - genetics Colonic Neoplasms - pathology Drug Synergism Humans Lung Neoplasms - drug therapy Lung Neoplasms - enzymology Lung Neoplasms - genetics Lung Neoplasms - pathology MAP Kinase Kinase Kinases - antagonists & inhibitors MAP Kinase Kinase Kinases - metabolism Mice Mice, Nude Mutation Protein Kinase Inhibitors - pharmacology Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins - metabolism Proto-Oncogene Proteins p21(ras) ras Proteins - genetics ras Proteins - metabolism Receptor, Epidermal Growth Factor - antagonists & inhibitors Receptor, ErbB-2 - antagonists & inhibitors Receptor, ErbB-2 - metabolism Receptor, ErbB-3 - biosynthesis Receptor, ErbB-3 - genetics Receptor, ErbB-3 - metabolism RNA, Small Interfering - administration & dosage RNA, Small Interfering - genetics Xenograft Model Antitumor Assays
ISSN:	2211-1247, 2211-1247
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Summary:	There are no effective therapies for the ~30% of human malignancies with mutant RAS oncogenes. Using a kinome-centered synthetic lethality screen, we find that suppression of the ERBB3 receptor tyrosine kinase sensitizes KRAS mutant lung and colon cancer cells to MEK inhibitors. We show that MEK inhibition results in MYC-dependent transcriptional upregulation of ERBB3, which is responsible for intrinsic drug resistance. Drugs targeting both EGFR and ERBB2, each capable of forming heterodimers with ERBB3, can reverse unresponsiveness to MEK inhibition by decreasing inhibitory phosphorylation of the proapoptotic proteins BAD and BIM. Moreover, ERBB3 protein level is a biomarker of response to combinatorial treatment. These data suggest a combination strategy for treating KRAS mutant colon and lung cancers and a way to identify the tumors that are most likely to benefit from such combinatorial treatment.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2211-1247 2211-1247
DOI:	10.1016/j.celrep.2014.02.045